Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Amgen Research (Munich) GmbH93 enrolled

Overview

The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.

Childhood acute lymphoblastic leukemia (ALL) is a type of cancer of the blood and bone marrow in which the bone marrow makes too many abnormal immature lymphocytes. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against cluster of differentiation (CD)19 expressing cells. The purpose of this study is to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of escalating doses of blinatumomab in pediatric and adolescent patients with relapsed/refractory B-precursor ALL, to select a dose and to investigate the efficacy and safety of that dose of blinatumomab in the above-mentioned patient population. The phase 1 part of the study included the evaluation of four dose levels of blinatumomab with comprehensive PK/PD assessments and was separated in 2 parts: * Phase 1 dose evaluation/escalation part to define the recommended phase 2 dose of blinatumomab in patients aged 2 to 17 years * Phase 1 PK expansion part in patients aged \< 18 years to further assess PK/PD at the recommended phase 2 dose. In this part additional participants were enrolled to ensure that 6 patients in each of the 2 older age groups (2-6 and 7-17 years) were analyzed for PK before recruitment of infants \< 2 years of age began. In the phase 2 extension cohort (efficacy phase) of the study, eligible participants less than 18 years were enrolled according to a two-stage design and received blinatumomab at the recommended dose level (5/15 μg/m²/day). The study consisted of a screening period, a treatment period, and an End of Core Study visit 30 days after last dose of study medication. A treatment cycle consisted of a continuous intravenous (cIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks. Participants who achieved complete remission (CR) within 2 cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Instead of consolidation cycles with blinatumomab, participants could be withdrawn from blinatumomab treatment to receive chemotherapy or allogeneic HSCT as early as the first cycle, at the discretion of the investigator. After the last treatment cycle and End of Core Study visit, all participants were followed for efficacy and survival for up to 24 months after treatment start. Participants who suffered a hematological relapse of B-precursor ALL during their follow-up period (at least 3 months after completion of treatment) had the possibility for retreatment with blinatumomab.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Lymphoblastic Leukemia

Interventions

BlinatumomabBIOLOGICAL

Administered by continuous intravenous infusion

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Morphologic evidence of B-precursor ALL with \> 25% blasts in bone marrow (M3) at study enrolment * Age less than 18 years at enrollment * Relapsed/refractory disease: * Second or later bone marrow relapse, * Any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or * Refractory to other treatments: Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration. Patients who have not achieved a first remission must have failed a full standard induction regimen * Karnofsky performance status more than or equal to 50% for patients more than or equal to 16 years and Lansky Performance Status (LPS) of more than or equal to 50% for patients less than 16 years * Organ function requirements: All patients must have adequate renal and liver functions Exclusion Criteria: * Active acute or extensive chronic graft-versus-host disease (GvHD) * Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment * Evidence for current central nervous system (CNS) involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL * History of relevant CNS pathology or current relevant CNS pathology * History of autoimmune disease with potential CNS involvement or current autoimmune disease * Any HSCT within 3 months prior to blinatumomab treatment * Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids) * Chemotherapy related toxicities that haven't resolved to less than or equal to Grade 2 * Radiotherapy within 2 weeks prior to blinatumomab treatment * Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment * Any investigational product within 4 weeks prior to study entry * Previous treatment with blinatumomab * Active severe infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol * Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)

Locations (30)

Outcomes

Primary Outcomes

Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)

The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.

Time frame: Cycle 1, 28 days

Percentage of Participants With Complete Remission in the First Two Cycles

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as * M1 bone marrow (bone marrow blasts \< 5%) * No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts.

Time frame: Cycles 1 and 2 (12 weeks)

Secondary Outcomes

Number of Participants With Adverse Events

The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following: Grade 1 - Mild adverse event; Grade 2 - Moderate adverse event; Grade 3 - Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

Time frame: From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days

Data from ClinicalTrials.gov

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